Certain types of pharmaceutically active ingredients cannot be administered orally due to subsequent alterations by the digestive system, and are thus generally administered parentally, e.g. intravenously or subcutaneously. In such a case, these pharmaceutically active ingredients have to be administered in liquid form. This is particularly the case for antibodies and other proteins that are large and complex molecules, as well as for certain chemical entities. However, antibodies and other large pharmaceutically active ingredients frequently have a poor stability in an aqueous environment, which may reduce the shelf life of the pharmaceutical composition to an unacceptable value.
Hence, it may be more advantageous in terms of stability, storage, and ease of shipping to prepare a solid form of the pharmaceutical composition, which may be reconstituted with a solvent shortly before its administration to a patient. Solid forms of pharmaceutical compositions that have to be administered in liquid form, e.g. through injection, are to be extemporaneously dissolved using an acceptable solvent composition to produce a solution for injection. Solid forms of pharmaceutical compositions include powders, freeze-dried (or lyophilized) compositions, spray-dried, spray-freeze dried, vacuum dried or supercritical fluid dried compositions.
The reconstitution steps may be carried out by the patient, a relative, a nurse or a healthcare professional, depending on the complexity of the reconstitution process. Typically it is preferable to use reconstitution processes which are relatively simple, reproducible and so would not require the presence of a healthcare professional. This is particularly true in cases of treatment of chronic diseases.
Although such reconstitution may be straightforward and as short as a few seconds for some specific compositions, it may take up to tens of minutes to reconstitute some others. Long reconstitution times involving complicated series of steps often lead to lower compliance with said protocols, and so finally can result in administration of a wrong dose and even potentially affect the outcome of the treatment.
Such hard and/or long to reconstitute solids generally have in common a poor wettability with respect to the solvent and/or a high final viscosity. Other frequent problems are the formation of foam, bubbles, creating a crown at the surface of the reconstituted pharmaceutical composition, gels or poorly wettable aggregates that require more time and attention for a careful reconstitution.
This is particularly the case for pharmaceutical compositions comprising high concentrations of large molecules, such as but not limited to monoclonal antibodies, polyclonal antibodies, certain recombinant proteins or polypeptides, steroid hormones and some large chemical entities such as antibiotics. It is also the case when the reconstitution is performed using less solvent volume than was originally taken out during processing towards a solid form, as is a common practice with formulations for injection so as to minimize the volume to be administered.
One can refer in this regard to the article by Pradip Hiwale et al. [1] which describes factors affecting reconstitution time of dry powder for injection and classifies them as intrinsic and extrinsic parameters.
In any case the most conventional manual process for reconstitution of a solid form of a pharmaceutical composition typically requires the following steps: retrieving the solvent from a first container, injecting it in a second container which contains the solid form of the pharmaceutical composition, homogenizing the liquid in the second container such that it is free of foam and/or dry aggregates, and withdrawing the reconstituted pharmaceutical composition from the second container for administration.
Each of these above-mentioned steps themselves may require several object manipulations, including needles or spikes, and the accomplishment of a defined process.
Depending on the manipulation steps applied and on the pharmaceutical composition, the reconstitution process may lead to a long reconstitution time, the presence of trapped dry lumps or gel zones that can hardly be reached by the solvent, the presence of trapped air bubbles or foaming, either in full volume or only limited to a ring at the air/liquid interface, and/or great variations in reconstitution times, each of which may be inacceptable for the reconstitution of the pharmaceutical composition.
In order to ensure the correct reconstitution and to reduce the user-to-user reconstitution deviations for pharmaceutical compositions, drug manufacturers provide users with an “Instructions for Use” leaflet to guide them in the process of reconstitution.
In most cases, the process includes a common solvent transfer phase, and for the homogenization several interwoven agitation/swirl and settling steps to wet the solid and observation of rehydration until complete dissolution is achieved, prior to final withdrawal. There may be recommendations of things “to do”, or “not to do”.
In addition, drug manufacturers may recommend a training for the user, may he/she be a professional or a patient or a relative or even limit the reconstitution to professionals.
For some lyophilized pharmaceutical compositions full reconstitution time may take as long as 30 minutes.
US 2011/0155620 describes that high or medium vacuum pressure (e.g. 100 Pa to 6×104 Pa) in vials filled with powder of a pharmaceutical composition helps to stabilize the composition during storage, facilitates the drawing of the solvent during reconstitution, evidences container closure integrity, possibly speeds up the reconstitution process and limits the production of foam.
WO 00/07539 teaches that foaming can be reduced by equalizing the pressure within the container with atmospheric pressure before introducing the solvent into the container; in this way, the solvent enters the container with less force and at a lower velocity.
However, despite the above-mentioned techniques, it is considered that the reconstitution of pharmaceutical compositions for administration remains a challenge, with respect to time but also other features. Hence, there remains a need in the art to further improve reconstitution processes for solid forms of pharmaceutical compositions.